This proposal addresses the critical question of which physiological mechanisms regulate the ability of an animal to select particular foods among a diverse array of macronutrients. The overall objective of this proposal is to examine the relative influence of post-absorptive, metabolic factors in contrast to gustatory input, on sugar and amino acid intake. More specifically, we will characterize a set of physiological responses that accompany amino acid vs. carbohydrate intake in both wild-type and genetically engineered taste-impaired mice. The physiological parameters to be monitored include the behavioral, calorimetric and neurochemical reactions that follow amino acid and carbohydrate consumption. Our central hypothesis states that the utilization of glucose as a metabolic fuel regulates nutrient preferences even when taste input is factored out. In other words, we hypothesize that the postingestive reward signals associated with sugars depend on the utilization of glucose as a cellular fuel. As a corollary, we specifically hypothesize that glucose utilization levels control extracellular dopamine concentration in striatum, given that nutrient preferences are ultimately regulated by dopamine signaling in this brain reward circuit. Testing this central hypothesis will involve employing behavioral, metabolic and neurochemical measurements in wild-type and Trpm5 knockout mice exposed to different carbohydrate and amino acid solutions. Importantly, by testing the glucose utilization hypothesis, the proposed project will provide novel data on how the metabolic and brain reward circuitry leads to the powerful motivation to consume sweet-tasting foods. The specific aims of this proposal are: 1 To characterize the role of glucose metabolism in postingestive reinforcement and 2 To characterize the role of glucose metabolism in the regulation of brain reward circuits. Consistent with our central hypothesis that glucose utilization favors carbohydrate intake over other nutrients, our preliminary studies allowed us to conclude that 1) KO mice show taste insensitivity to some several sugars and L-amino acids while displaying increased preferences for glucose compared to L-amino acid solutions in a way that is independent of taste input; 2) Glucose utilization rates are efficient predictors of sugar intake levels independently of taste input; 3) Sweet-impaired Trpm5 knockout mice attribute increased reward value to glucose when its ingestion counteracts the effects of glycolysis inhibition; 4) Dopamine levels in brain reward circuitries are sensitive to compounds that favor higher glucose utilization levels independently of orosensory stimulation; 5) Dopamine levels in these regions are negatively affected by glycolysis inhibition; 6) Trpm5 knockout mice display normal metabolization and absorption of ingested carbohydrate and proteins; in addition, differential behavioral responses to sugars and amino acids are not accounted for solely by gastrointestinal sensing and absorption. We believe that our studies will contribute to establishing an integrative physiology of sugar reward, an important and yet underrepresented area of research. PUBLIC HEALTH RELEVANCE: Uncovering sweet-independent reward signals favoring carbohydrate intake might significantly further our understanding on the reciprocal roles of gustatory and metabolic signals in stimulating the excessive consumption of sugars observed worldwide. In fact, there are several lines of evidence to suggest that currently undetermined sweetness-independent signals produced during glucose metabolism function to reinforce carbohydrate intake. Our work may provide new insights on the exact roles of taste quality and metabolism in sugar overconsumption.